Keywords

Abstract

The epidemic of cardiovascular disease being experienced by developing countries has resulted in a debate about the possible existence of regional differences in etiology and pathophysiology that could be associated with socio-economic factors. Clear demonstration of these differences is important because there may be a need for different approaches to prevention, diagnosis and treatment. There is some evidence that there are differences between populations in developed and developing countries in the pathophysiologic mechanisms underlying pregnancy-induced hypertension and metabolic syndrome, just as there are in the relative weightings of risk factors that predict the appearance of these conditions. Observations in our country suggest that increasing exposure to changes in lifestyle brought about by the consumer society (e.g., a lack of exercise, and a high-fat, high-calorie diet) results in a natural biological response (e.g., obesity, metabolic syndrome, and diabetes) that increases the risk of cardiovascular disease. We propose that the term socioeconomic pathology should be used to describe these changes associated with modern society so that they can be differentiated and considered in isolation from socioeconomic factors and other risk factors. We regard the interaction between these various factors as the most important cause of the rapidly increasing incidence of cardiovascular disease observed in developing countries in recent years.

Article

INTRODUCTION

The rapid
increase in the incidence of cardiovascular disease (CVD), which
has taken on epidemic proportions in developing
countries,1,2 has led to debate as to whether findings
from research in the developed world are applicable in the
developing world.

The present
article reviews a series of studies in the United States, Spain,
Colombia, and Ecuador which suggest that the etiophysiopathology
and the specific importance of risk factors for CVD, particularly
metabolic syndrome and pregnancy induced hypertension, differ
between developed and developing countries.

THE "EPIDEMIOLOGIAL TRANSITION"

Differences in
the epidemiological profile of diseases affecting developed and
developing countries can be due to diverse geographical,
environmental, demographic, socio-economic, and ethnic
characteristics.3 Until a few years ago, the leading
causes of death in developing countries, particularly in childhood,
were malnutrition, tropical, and perinatal diseases (Table
1).4-6 Adequate control of these diseases has led to an
increase in life expectancy in Ecuador from 48.4 to 70.8 years in
2005.7 In Colombia, life expectancy has increased from
55 to 72.2 years over the last 50 years.7 These data
compare to increases in life expectancy in the United States and
Spain from 68.9 to 77.1 and 63.9 to 79.3 years, respectively, for
the same period (Figure 1).7 The ageing of Colombia's
population is reflected in the fact that, in 1951, 2.8% of the
population was aged 65 years or over compared to 4.4% in
1993.8

Figure 1.
Changes in life expectancy at birth
in Spain, the United States, Colombia, and Ecuador for the period
1955-2005. In the United States and Spain, life expectancy has
stabilized in the last few decades after reaching a plateau at
around 75 years. In the Andean countries, an increase in life
expectancy can be observed for the same period.

Whilst the
incidence of CVD is tending to stabilize or decrease in the
developed world9-11 and prognosis is
improving,12 in the developing world the incidence is
increasing. Mortality data from Ecuador shows that over a period of
barely 20 years, cerebrovascular disease rose from ninth to second
place as a leading cause of death between 1975 and
1995.13 In the same year, hypertension (in third place),
diabetes mellitus (DM) in fifth place, and acute myocardial
infarction (AMI) in eighth place, also became some of the leading
causes of death. Together, these 3 disease caused 3 times more
deaths than pneumonia, which was the leading cause of death in 1995
(Table 1).13 A similar pattern has been observed in
Colombia, where AMI, cerebrovascular accident, and DM caused 213
150 deaths (19.6%) over the period 1997-2001.8 In
combination, mortality from CVD was greater than that from violent
causes and CVD is among the 10 leading causes of death in both men
and women (Table 2).14 The question that arises is what
has caused this shift. Is it only increased access to health care
and the quality of that care?

Several studies
have looked at the epidemic behavior of CVD in underdeveloped
countries.15,16 The INTERHEART study17 aimed
to identify the effect of modifiable risk factors associated with a
first AMI and included 12 461 patients with a first acute coronary
event and 14 637 controls from 52 developed and developing
countries, including Colombia. The study showed that a raised apo
B/apo A1 ratio, smoking, diabetes, hypertension, abdominal obesity,
psychosocial stress (calculated using a combination of scores
relating to depression, stress in the workplace or at home, and
financial stress) were all positively associated with having an
AMI, while the adequate consumption of fruit and vegetables,
moderate alcohol consumption, and exercise were all associated with
a lower risk of having such an event. The study also showed that
there were no significant differences in the prevalence of these
risk factors between developed and developing
countries.17 High-calorie, high-fat diets which are low
in fiber have become commonplace in recent years in developing
countries18 and this, coupled with the increasing
physical inactivity which has accompanied urbanization, has helped
to produce the increase in obesity, particularly abdominal
obesity,19 which has been observed in Latin American
countries (Figure 2).19-21 Abdominal obesity together
with 2 other risk factors constitutes the metabolic syndrome (MS)
which has been defined by the International Diabetes Federation
(IDF)22 as: hypertension (>130/85 mm Hg), raised
triglycerides (>150 mg/dL), reduced HDL cholesterol (HDL-C,
<50 mg/dL in women and <40 mg/dL in men), and fasting plasma
glucose >100 mg/dL.

Figure 2.
Prevalence of overweight and obesity
in different Latin American countries, Spain, and the United
States. BMI indicates body mass index.

Recent studies
have consistently shown that MS is associated with an increased
risk of CVD and type 2 diabetes.23-25 It is also
important to note the IDF's insistence on abdominal obesity as an
essential element in the diagnosis of MS and their use of different
cut points for waist circumference according to country and
race.22,26

BIOLOGICAL MECHANISMS UNDERLYING THE METABOLIC
SYNDROME

In Figure 3, we
present a proposed general outline which relates socioeconomic
factors to some of the biological mechanisms involved in the onset
of MS. The response to the socioeconomic model imposed in
Iberoamerican countries has been a massive migration from the
countryside to industrialized urban centers. In Colombia, the
process of urbanization has been further accelerated by the forced
displacement of entire rural communities fleeing the armed
conflict.27 Currently, over 70% of the population lives
in urban centers.28 The process of urbanization is also
a response to modernization and the attractions of the new, western
lifestyle for rural populations.18

Figure 3.
Mechanisms possibly participating in
the genesis of metabolic syndrome and cardiovascular mortality in
developing countries. Inequalities deriving from the consumerist
society lead to rapid urbanization which causes profound changes in
eating habits and physical activity. These in turn produce obesity,
particularly abdominal obesity, which sets off a chain of
physiopathological events leading to endothelial dysfunction and an
increase in diseases such as hypertension, type 2 diabetes mellitus
and metabolic syndrome. These contribute to the increase in
mortality due to coronary events. IL-6 indicates interleukin-6;
NADPHox, nicotinamide adenine dinucleotide phosphate oxidase; CRP,
C-reactive protein; IR, insulin resistance; TNF
α
, tumor
necrosis factor alpha.

Urbanization has
been accompanied by radical modifications in lifestyle,
including29,30:

1. A
shift from a diet which is rich in vegetables, cereals, and fruit
to a western, fast-food diet, with a high fat and calorie and low
fiber content (hamburgers, french fries, pizza, soft
drinks).

2. A
reduction in physical activity associated with the mechanization of
daily activities and changes in leisure activities, particularly in
children. Thus, in cities, the washing machine, gas cookers,
elevators, the subway, computers, and "Play Stations" have replaced
the collection of firewood, the sowing and harvesting of food, and
traditional games which required physical effort.

The result of
these changes has been an increase in the prevalence of obesity,
initially abdominal obesity. The populations of developing
countries are often short in stature, probably as a result of
having only limited nutritional resources for
generations.31 They also present a characteristic
phenotype, particularly among men, who are characteristically
"short and tubby." Visceral adipocytes produce a low-grade chronic
inflammatory state characterized by an increase in the circulating
concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha
(TNF
α
), and C-reactive protein
(CRP).32,33 This low grade inflammation leads to
dysfunction of the endothelial cells, which lose their
vasodilatory, antithrombotic, and antiatherogenic
properties34,35; this is apparently a widespread
biological response in humans.36-39 The question then is
why the populations of developing countries should be more
sensitive to this process. We suggest that this is a result of the
lower exposure time among the populations of developing countries
to the new lifestyles associated with modernization. The shorter
the exposure time, the less adapted the population, and the greater
the risk of an inflammatory response at lower levels of abdominal
obesity. This is in turn associated with an increased risk of type
2 diabetes and CVD. Figure 4 shows data which illustrate the
positive relationship between plasma levels of inflammation markers
and waist circumference in healthy individuals in Colombia and in
individuals with hypercholesterolemia with and without MS. We have
also reported that increased levels of inflammatory

Figure 4.
Behavior of tumor necrosis factor
alpha (TNF
α
and flow-mediated vasodilatation in
healthy individuals and individuals with hypercholesterolemia with
and without metabolic syndrome. Plasma levels of TNF
α
and flow-mediated vasodilatation, in healthy Colombian individuals
and those with hypercholesterolemia with and without metabolic
syndrome. Increases in TNF
α
levels parallel increases
in waist circumference, while the endothelial function is
significantly reduced. WC indicates waist circumference; MS,
metabolic syndrome.

markers and
increased risk of pregnancy induced hypertension and CVD are
present in the Andean population at lower levels of abdominal
obesity.40-42 We have also shown that the the leukocyte
count and concentrations of ultrasensitive CRP were significantly
greater in individuals with a waist circumference >88
cm,43 and that CRP concentration is a risk factor for
essential hypertension and pregnancy induced hypertension in the
Andean population.40-42 It is well-known that the
Hispanic population in the United States and that the Hindu
population in the United Kingdom are at greater risk for low-grade
chronic inflammation, type 2 DM, and cardiovascular mortality than
the Caucasian populations of those countries.36-39,44
However, it is currently not clear whether these differences are
due to genetic or socioeconomic factors, as these groups migrated
relatively recently to developed countries and have therefore only
had a short exposure to risk factors and are anyway usually in
lower socioeconomic categories. Although there are no data from
studies which have specifically investigated this problem, we
believe that length of exposure to the new living conditions
generated by urbanization and modernity is an important risk factor
for minority populations in developed
countries.45-48

The recent
large-scale migration of indigenous Ecuadorians to Spain provides
an excellent opportunity to study this possibility. Amongst the
population of Colombia, which includes a range of well-defined,
different races, though also substantial intermixing between races,
we did not find the marked differences in prevalence of MS between
races that has been observed in developed
countries.49,50 The Pima Indians provide a striking
example of the relationship between environment and genetics: as
indigenous Indians living in the United States and exposed to a
consumer society lifestyle they experienced an explosive increase
in obesity, MS, type 2 diabetes, and CVD, whilst the Pima Indians
living in Mexico within a more traditional lifestyle did not
experience this dramatic increase.45-48 At the same
time, there have been important developments in epigenomics, or the
study of the impact of environment in the expression of genes
participating in the metabolism of nutrients and
energy.51

HEALTH CARE INFRASTRUCTURE, INFECTION, AGEING AND
CARDIOVASCULAR RISK

Although
abdominal obesity is considered the most important risk factor for
the low-grade chronic inflammation associated with the development
of endothelial dysfunction, MS, atherosclerosis, type 2 DM, and
CVD, it appears that the presence of other factors such as chronic
infections, which are very frequent in developing countries due to
inadequate health care systems, could also play a
part.52,53 Several studies have shown that recent
infection of the lower respiratory tract and the urinary tract
increases the risk of CVD.54,55

In Iberoamerican
countries, the bad habits and defects of the two worlds have
collided: lack of potable water, defective waste and sewage
removal, high rates of intestinal parasitism, non-preventable
infections, and tropical diseases are all still present, but are
now coupled with diets which are high in saturated fats and refined
flours, more smoking, higher rates of physical inactivity, and
obesity.56

In recent
decades, the proportion of elderly has also increased.8
The ageing process involves greater activity of the
renin-angiotensin system, a hormone which has 3 important effects
in humans57-60:

1. It
increases the oxidative stress in the vascular wall, which causes
increased inactivation of oxygen free radicals and therefore alters
the balance of these substances, leading to endothelial
dysfunction.61

3. It
stimulates the production of pro-inflammatory cytokines, such as
TNF
α
, in adipocytes and
endothelial cells. This in turn activates metalloproteinase 2, an
enzyme which breaks down the stable atherosclerotic plaque, thereby
producing an atherothrombotic profile which is key to the
presentation of acute myocardial
infarction.62

Altered
endothelial function is essential to the development of
atherosclerotic plaque, the pro-coagulant state, increased vascular
tone, and arterial hypertension and insulin resistance, all of
which are associated with MS and increased risk of
CVD.34,35,63

METABOLIC SYNDROME: ETIOLOGICAL AND DIAGNOSTIC
DIFFERENCES

In the
populations of Colombia and Ecuador,43,64,65 there
appears to be an increased risk of MS at a lower grade of abdominal
obesity than that set out in the Third Panel on the Treatment of
Adults in the United States' National Cholesterol Education Program
(ATP-III).66 Among Colombian males serving in the army,
it was found that a waist circumference of 88 cm had greater
sensitivity and specificity than the 94 cm recommended in Caucasian
subjects to identify individuals with the so-called atherogenic
profile, a profile characterized by an increase in triglyceride
levels, insulin and glucose, and low levels of HDL cholesterol
(HDL-C).43 In male employees of the Ecuador Petrol
Company, it was found that a waist circumference of 90 cm best
identified individuals meeting other criteria for a diagnosis of
MS.65 A cut-point of 90 cm had a sensitivity and
specificity of 83.9% and 70.3%, respectively, with positive and
negative predictive values of 60.2% and 88.6%, respectively. In
contrast, when the threshold recommended by the ATP-III for North
Americans (102 cm) was used, sensitivity was barely 23.2%, with a
specificity of 96%.65 These results indicate that when
diagnosing MS in these Andean populations it is more convenient to
use the IDF criteria. We later demonstrated that 50% of individuals
with a history cardio-cerebrovascular events (n=670) had a
diagnosis of MS independently of the diagnostic criteria used
(ATP-III or IDF),64 making discussion as to which
criteria to use irrelevant in this population. However, in
individuals with no prior history of cardio-cerebrovascular events
(n=583), use of the IDF criteria led to a diagnosis of MS in 41.4%
of those studied compared to 31.2% using the ATP-III criteria
(P<.0001). At present, no prospective studies have been
performed to determine whether a diagnosis of MS in these
populations is associated with greater risk of CVD or DM2. In a
recent study performed in Spain, Alegría et al67
determined that the raw prevalence of MS in the adult working
population of Spain was 10.2%, and that it was higher in
individuals with any type of fasting glucose alteration and in
those with a higher body mass index.

Ford recently
included data from cohort studies in the United States in a
systematic review to estimate the relative risk for all-cause
mortality, cardiovascular disease, and diabetes associated with the
metabolic syndrome in the general adult population, and using the
definitions of MS proposed by the ATP-III and the World Health
Organization (WHO).23 Using the ATP-III definition, the
combined relative risk was 1.2 (95% confidence interval [CI],
0.90-1.78) for all cause mortality, 1.6 (95% CI, 1.3-1.9) for
cardiovascular disease, and 2.9 (95% CI, 1.9-4.5) for DM. The
author concluded that, in the United States population, MS defined
using the ATP-III or WHO criteria has limited predictive capacity
for all-cause mortality or CVD, and that it is better at predicting
development of type 2 DM.23 Recently, the same author
showed that in 3601 North American adults of both sexes, the
unadjusted prevalence of MS was 39.0% using the IDF criteria and
34.5% using the ATP-III definition.68 The difference was
greater in American-Mexican males, who had an age-adjusted
prevalence of 50% using the IDF criteria compared to 40.3% using
the ATP-III definition. It had been previously shown that this
group was at greater risk of developing type 2 DM and
CVD.19,27 This group's socioeconomic conditions are
poorer than those of other ethnic groups, and they have also lived
in the United States for only a few years, and therefore have only
been exposed to a highly consumerist society for a relatively short
time.69 Katzmarzyk et al70 recently evaluated
the ability of the ATP-III and IDF criteria to predict all-cause
mortality and cardiovascular mortality in 20 789 non-Hispanic
males. Mean age at study entry was 43.3 years, and the prevalence
of MS at study commencement was 19.7% using the ATP-III criteria
and 30.0% using the IDF criteria. A diagnosis of MS was associated
with a relative risk (RR) of death from any cause 1.3 (95% CI,
1.1-1.6) when the ATP-III criteria were used and 1.2 (95% CI,
1.0-1.4) using the IDF criteria. The RR for death from CVD was 1.7
(95% CI, 1.3-2.3) using the ATP-III criteria and 1.6 (95% CI,
1.2-2.2) using the IDF criteria. To determine the impact of
abdominal obesity on mortality, individuals with a waist
circumference <94 cm and >102 cm were evaluated. A direct
relationship was found between waist circumference and an increased
RR of death from CVD, particularly in individuals who also had 2 or
more metabolic risk factors (94-102 cm: 1.5; 95% CI, 1.0-2.3;
>102 cm: 2.3; 95% CI, 1.5-3.4). In males over 18 years of age
who participated in the National Health and Nutrition Examination
Survey (NHANES), the prevalence of MS using the ATP-III definition
was 24.3% and 38.6% using the IDF definition. The population
attributable fraction for MS varied from 8.0% to 9.1% for all-cause
mortality, and from 16.1% to 20.5% for mortality associated with
CVD, whichever criteria were used. These data are similar to those
reported recently in the Hoorn study24 which showed that
a diagnosis of MS doubled the risk of CVD, regardless of which
criteria were used to define MS.

Lawlor et
al71 analyzed data from a cohort of 3589 British women
aged 60-79 with no history of CVD, and reported the prevalence of
MS to be 48% using the IDF criteria and 29% using the ATP-III
criteria. The age-adjusted RR for MS was similar using the IDF and
ATP-III criteria. The authors found that, using either of the
definitions, MS showed a modest association with risk of CVD; after
correcting for smoking, physical inactivity, and socio-economic
position, the association decreased to 1.25 and 1.27, respectively.
The authors concluded that MS is only weakly associated with CVD
risk and questioned the importance of MS as a risk factor for CVD.
With regard to the proposal set out here for a socio-economic
pathology, it is interesting to note that the most important
confounding factor in the association between MS and CVD risk was
socio-economic position. This factor was more important than
smoking and physical inactivity, not only in terms of attenuating
the impact of MS on CVD risk, but also in terms of reducing the
linear association between CVD risk and insulin resistance,
triglyceride levels, HDL-C, and the waist-hip ratio. Other studies
have shown that MS prevalence is inversely related to
socio-economic level, although statistical significance was not
reached.67

Our studies in
Colombia and Ecuador, although cross-sectional in design, support
the IDF notion of the MS as clinically useful and suggest that
health-care teams in those countries should use it to help identify
individuals who could benefit from multifactorial preventive
programs to reduce the risk of CVD and type 2 DM. The differences
with results from North America, the United Kingdom, and Spain may
be due to the socio-economic differences between those countries
and the Andean populations covered in our studies. The idea that
the interaction between socio-economic conditions and the classic
cardiovascular risk factors depends on the degree of development of
a given society and the length of exposure to the consumer society,
and that it is this interaction that determines the overall degree
of risk for CVD, is what we have proposed should be called the
"socioeconomic pathology," to differentiate it from the study of
individual risk factors in isolation.

REGIONAL DIFFERENCES IN THE ONSET OF PREGNANCY INDUCED
HYPERTENSION

Pregnancy
induced hypertension (PIH) has physiopathological characteristics
which are similar to those of atherosclerosis and CVD but, unlike
them, it has a rapid onset and evolution, with clinical
manifestations appearing during the second half of the pregnancy
and resolving abruptly after childbirth.72 There are
enormous differences between developed and developing countries in
the incidence of PIH and its contribution to maternal mortality.
Mortality in the USA and Europe is 10 per 100 000 live births, in
Latin America it is 220 per 100 000 live births and in Africa it is
430 per 100 000 live biths.73 These figures appear to be
determined by the marked socio-economic differences, and by the
deficient health-care systems and sanitary conditions in developing
countries coupled with fact that nutritional resources, especially
of dietary minerals, are inadequate to meet the greater demand
occasioned by the growth of the fetus.72,74-76 The level
of socio-economic development in developed countries means that
adequate prenatal control is available for most women during
pregnancy. This includes the early diagnosis and treatment of
urinary, vaginal and oral infections, as well as access to an
adequate diet and the necessary mineral and vitamin
supplements.74 In Ecuador and Colombia, a high
proportion of women do not have access to adequate prenatal
control, and infections and diet deficiencies are neither detected
nor corrected. This is a socioeconomic pathology which leads to a
high risk of PIH and maternal mortality.72 In these
Andean countries, early diagnosis and effective treatment of
sub-clinical vaginal and urinary infections during pregnancy, and
adequate dietary supplements with calcium and linoleic acid, reduce
the risk of PIH to levels similar to those observed in developed
countries.77-82 When nutritional and infectious factors
have been controlled in these women, obesity, dysglycemia, and
dyslipidemia become the main risk factors for preeclampsia
(PE).77,78 Thus, about 95% of the risk for PIH in
Colombian and Ecuadorian women could be controlled by diagnosing
and curing oral, urinary and vaginal infections, assuring an
adequate intake of macronutrients and vitamin and mineral
supplements, and by using diet and physical exercise to control
excess weight gain and lipid and glucose alterations.72
The remaining 5% of risk for PIH may be due to genetic and
immunologic factors, including polymorphic alterations in the
nitric oxide synthase gene, which is important in these
countries.83 Further support for the proposal set out
here is provided by the fact that in the populations of
Colombia84 and Ecuador,85 the levels of
asymmetric dimethylarginine (ADMA), an endogenic inhibitor of
nitric oxide synthase, plays no part in the development of PIH,
whilst several European studies demonstrated that ADMA plays an
important role in PIH.86,87 The difference may be due to
environmental factors, such as malnutrition and infections, which
reduce the impact of ADMA as a risk factor for PIH in Colombian and
Ecuadorian women. On the basis of these findings, we propose that
the fundamental cause of the increased risk for PIH among
populations of developing countries are the social and economic
inequalities which impede the provision of adequate health care and
prenatal control. This in turn would explain the enormous regional
differences seen in the incidence and mortality due to
PIH.72

HYPOTHESES AND PERSPECTIVES

The current
epidemic of obesity, DM and CVD in developing countries appears to
be a natural human biological response to the imposition of
lifestyles for which we are not particularly well adapted. Our
proposal is that the differences in the patterns of CVD
morbimortality rates between the developed and the developing world
are dependent on the length of exposure to the socio-economic
pathology and the degree of adaptation to that pathology. If this
proposal, which requires further study, is confirmed, it could lead
to fundamental changes in health policy and preventive programs for
CVD and type 2 DM, for example by taking into account that
diagnostic criteria and preventive and treatment strategies should
not necessarily be uniform in populations with different levels of
socioeconomic development and in which there are enormous social
and economic inequalities. For Iberoamerican countries, the big
challenge will be to carry out large-scale, prospective research
which will allow them to develop their own diagnostic criteria and
the most useful preventive and therapeutic strategies. The recent
large-scale migrations of native Ecuadorians to Spain will provide
an interesting model for the study of the interaction between
genetics and environment, and will have important repercussions for
the Spanish health care system.